Pharmacogenomic profiling reveals molecular features of chemotherapy resistance in IDH wild-type primary glioblastoma

Abstract

Background Although temozolomide (TMZ) has been used as a standard adjuvant chemotherapeutic agent for primary glioblastoma (GBM), treating isocitrate dehydrogenase wild-type (IDH-wt) cases remains challenging due to intrinsic and acquired drug resistance. Therefore, elucidation of the molecular mechanisms of TMZ resistance is critical for its precision application. Methods We stratified 69 primary IDH-wt GBM patients into TMZ-resistant (n = 29) and sensitive (n = 40) groups, using TMZ screening of the corresponding patient-derived glioma stem-like cells (GSCs). Genomic and transcriptomic features were then examined to identify TMZ-associated molecular alterations. Subsequently, we developed a machine learning (ML) model to predict TMZ response from combined signatures. Moreover, TMZ response in multisector samples (52 tumor sectors from 18 cases) was evaluated to validate findings and investigate the impact of intra-tumoral heterogeneity on TMZ efficacy. Results In vitro TMZ sensitivity of patient-derived GSCs classified patients into groups with different survival outcomes (P = 1.12e−4 for progression-free survival (PFS) and 3.63e−4 for overall survival (OS)). Moreover, we found that elevated gene expression of EGR4, PAPPA, LRRC3, and ANXA3 was associated to intrinsic TMZ resistance. In addition, other features such as 5-aminolevulinic acid negative, mesenchymal/proneural expression subtypes, and hypermutation phenomena were prone to promote TMZ resistance. In contrast, concurrent copy-number-alteration in PTEN, EGFR, and CDKN2A/B was more frequent in TMZ-sensitive samples (Fisher’s exact P = 0.0102), subsequently consolidated by multi-sector sequencing analyses. Integrating all features, we trained a ML tool to segregate TMZ-resistant and sensitive groups. Notably, our method segregated IDH-wt GBM patients from The Cancer Genome Atlas (TCGA) into two groups with divergent survival outcomes (P = 4.58e−4 for PFS and 3.66e−4 for OS). Furthermore, we showed a highly heterogeneous TMZ-response pattern within each GBM patient using in vitro TMZ screening and genomic characterization of multisector GSCs. Lastly, the prediction model that evaluates the TMZ efficacy for primary IDH-wt GBMs was developed into a webserver for public usage (http://www.wang-lab-hkust.com:3838/TMZEP). Conclusions We identified molecular characteristics associated to TMZ sensitivity, and illustrate the potential clinical value of a ML model trained from pharmacogenomic profiling of patient-derived GSC against IDH-wt GBMs.

RND1 inhibits epithelial-mesenchymal transition and temozolomide resistance of glioblastoma via AKT/GSK3-β pathway

“…On the other hand, intra-tumoral heterogeneity is an important factor in GBM’s resistance to TMZ or other therapies. 43 It is probably attributed to the presence of multiple subclone tumor cells and non-neoplastic cells, including infiltrating and resident immune cells, vascular cells, and other glial cells, which have the ability to evade chemotherapy and regenerate tumors in GBM. 44 Our in vitro and in vivo experiments were conducted in U87 and U251 cell lines, which cannot reflect the complex and heterogeneous status of GBM.…”

Clinical Application of the Association between Genetic Alteration and Intraoperative Fluorescence Activity of 5-Aminolevulinic Acid during the Resection of Brain Metastasis of Lung Adenocarcinoma

“…To the best of our knowledge, few comprehensive studies have demonstrated the genetic and molecular characteristics of infiltrative BM according to the fluorescence activity of 5-ALA. Several studies have focused on the role of 5-ALA in glioblastoma [ 41 , 42 , 43 , 44 ]. For example, negative 5-ALA fluorescence has been reported to promote temozolomide resistance [ 41 ], and different patterns of immune infiltration have been found according to 5-ALA signatures by analyzing TCGA mRNA data [ 42 , 43 ].…”

“…To the best of our knowledge, few comprehensive studies have demonstrated the genetic and molecular characteristics of infiltrative BM according to the fluorescence activity of 5-ALA. Several studies have focused on the role of 5-ALA in glioblastoma [ 41 , 42 , 43 , 44 ]. For example, negative 5-ALA fluorescence has been reported to promote temozolomide resistance [ 41 ], and different patterns of immune infiltration have been found according to 5-ALA signatures by analyzing TCGA mRNA data [ 42 , 43 ]. Positive 5-ALA gene signatures, which were analyzed by spatially resolved bulk RNA profiling, showed transcriptionally concordant glioblastoma and myeloid cells with mesenchymal subtype to be associated with poor survival and recurrence of glioblastoma [ 44 ].…”

Intradural Intramedullary Spinal Cord Glioblastoma: A Case Report

“…In particular, IDH-wt glioblastoma that was diagnosed in our patient constitutes the most common and aggressive GBM subtype [ 7 ]. By definition, these glioblastomas lack mutations in IDH1/2 and are classified as IDH-wt glioblastoma per the 2021 WHO revision.…”